ABSTRACT

There has been increasing recognition of the problem of fatal opioid
overdose. This review examines the pharmacological basis of respiratory
depression following opioid administration. Respiration is controlled
principally through medullary respiratory centres with peripheral input from
chemoreceptors and other sources. Opioids produce inhibition at the
chemoreceptors via mu opioid receptors and in the medulla via mu and delta
receptors. While there are a number of neurotransmitters mediating the control
of respiration, glutamate and GABA are the major excitatory and inhibitory
neurotransmitters, respectively. This explains the potential for interaction of
opioids with benzodiazepines and alcohol: both benzodiazepines and alcohol
facilitate the inhibitory effect of GABA at the GABAA receptor, while alcohol
also decreases the excitatory effect of glutamate at NMDA receptors. Heroin and
methadone are the major opioids implicated in fatal overdose. Heroin has three
metabolites with opioid activity. Variation in the formation of these
metabolites due to genetic factors and the use of other drugs could explain
differential sensitivity to overdose. Metabolites of methadone contribute little
to its action. However, variation in rate of metabolism due to genetic factors
and other drugs used can modify methadone concentration and hence overdose risk.
The degree of tolerance also determines risk. Tolerance to respiratory
depression is less than complete, and may be slower than tolerance to euphoric
and other effects. One consequence of this may be a relatively high risk of
overdose among experienced opioid users. While agonist administration modifies
receptor function, changes (usually in the opposite direction) also result from
use of antagonists. The potential for supersensitivity to opioids following a
period of administration of antagonists such as naltrexone warrants further
investigation. While our understanding of the pharmacological basis of
opioid-related respiratory depression has advanced, better understanding of the
role of heroin metabolites, the metabolism of methadone, drug interactions and
tolerance would all be of considerable value in knowing how best to respond to
this problem.